tbuckley/cabot-search huggingface dataset:
Abstract 4183: Differential modulation of tumor versus T cell oxidative phosphorylation potentiates anti-tumor immunity
Authors: Krithikaa Rajkumar Bhanu, Priyamvada Jayaprakash, Meghan Rice, Brittany Morrow, Joseph R. Marszalek, Jason P. Gay, Christopher P. Vellano, Benjamin R. Cowen, Dean J. Welsh, Michael A. Curran
Journal: Cancer Research (2022)

Abstract We sought to determine whether various inhibitors of Oxidative Phosphorylation (OxPhos) could restore tumor infiltrating T cell functionality and longevity while compromising metabolic fitness of tumor cells. Using a combination of in vitro metabolic profiling with the Seahorse XFe96 Analyzer and in vivo tumor immunotherapy in the immunocompetent TRAMP-C2 prostate adenocarcinoma model, we determined the differential impact of multiple OxPhos inhibitors on both tumor immune metabolic fitness and functional capacity. Impact on the tumor immune microenvironment of TRAMP-C2 tumors was assessed through high parameter flow cytometry on a BD X-30. While OxPhos inhibition compromised initial T cell activation, we found that two of the inhibitors increased the glucose uptake, proliferation, and activation status of effector T cells. In contrast, the same two inhibitors decreased the mitochondrial fitness, proliferation and OxPhos metabolic capacity of TRAMP-C2 tumor cells themselves. To determine whether this selective inhibition of tumor versus T cell metabolic function could improve immunotherapy responses in vivo, we implanted TRAMP-C2 tumors and treated them with these OxPhos inhibitors with or without concomitant immune checkpoint blockade (ICB). The combination of ICB and OxPhos inhibition achieved highly significant and durable rates of tumor control and regression suggesting that these approaches are potentially synergistic. Analysis of the tumor microenvironment has identified the cellular mechanisms underlying these therapeutic effects which may provide useful biomarkers as this novel combination is translated to the clinic. Citation Format: Krithikaa Rajkumar Bhanu, Priyamvada Jayaprakash, Meghan Rice, Brittany Morrow, Joseph R. Marszalek, Jason P. Gay, Christopher P. Vellano, Benjamin R. Cowen, Dean J. Welsh, Michael A. Curran. Differential modulation of tumor versus T cell oxidative phosphorylation potentiates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4183.
Abstract 6368: Discovery of potent, orally bioavailable, SOS1 inhibitors for KRAS-driven tumors
Authors: Sanjita Sasmal, Sukanya Patra, Venkatesham Boorgu, Mahesh Yanamadra, Ashok Ettam, Nagaraju Dunaboyina, Githavani Kummari, Ram Mohan Yengala, Balakrishna Lakhavath, Jayita Das, Satheesh Sunkanapally, Pravalika Reddy, Megha Mariam Mathew
Journal: Cancer Research (2022)

Abstract KRAS is an oncogene implicated in a wide variety of tumors (~21% of solid tumors harbor KRAS mutations). KRAS interaction with Guanidine Exchange Factors (GEFs) is crucial for its activation, with SOS1 being the predominant GEF. SOS1 inhibition is thus expected to be an effective strategy for targeting the downstream signaling pathway, resulting in anti-proliferative activity in RAS-driven cancers. We have identified multiple potent and selective SOS1 inhibitors, demonstrating significant reduction of GEF activity in a dose-dependent manner. The lead compounds show anti-proliferative activity across a panel of WT and mutant KRAS cell lines, and are synergistic with MAPK pathway inhibitors including KRASG12C inhibitor Sotorasib. Correspondingly, significant reduction in PD biomarkers, pERK and pAKT is demonstrated in KRAS mutant cell lines. PK-PD correlation is also established in a tumor bearing mice model, with dose-dependent reduction of both pERK and pAKT. The lead compound shows good ADME properties, and is orally bioavailable, making it amenable for further in vivo profiling. Citation Format: Sanjita Sasmal, Sukanya Patra, Venkatesham Boorgu, Mahesh Yanamadra, Ashok Ettam, Nagaraju Dunaboyina, Githavani Kummari, Ram Mohan Yengala, Balakrishna Lakhavath, Jayita Das, Satheesh Sunkanapally, Pravalika Reddy, Megha Mariam Mathew. Discovery of potent, orally bioavailable, SOS1 inhibitors for KRAS-driven tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6368.
Abstract 1151: Pharmacogenomics genotyping from clinical somatic whole exome sequencing: Aldy, a computational tool
Authors: Wilberforce A. Osei, Tyler Shugg, Reynold C. Ly, Steven M. Bray, Benjamin A. Salisbury, Ryan R. Ratcliff, Victoria M. Pratt, Ibrahim Numanagić, Todd Skaar
Journal: Cancer Research (2022)

Abstract Background Pharmacogenomics (PGx) testing can reduce toxicities and improve efficacy of several drugs used to treat cancer and associated symptoms. PGx results can be determined from germline whole-exome sequencing (WES), but somatic mutations may cause discordance between tumor and germline DNA. Since clinical diagnostic sequencing in oncology frequently only includes tumor DNA, there would be clinical value in calling germline PGx genotypes from tumor DNA. Thus, the purpose of this study was to assess the feasibility of using somatic WES data to call germline PGx genotypes. Methods Germline and somatic WES data were obtained as part of the clinical workflow for 64 patients treated at the solid molecular tumor board clinic at Indiana University. Aldy v3.3 was implemented in LifeOmic’s Precision Health Cloud™ to call PGx genotypes from somatic WES. Somatic Aldy calls were compared with previously validated Aldy germline calls for 8 genes: CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP4F2, DPYD, and TPMT. Somatic read depth was &amp;gt;100x, except for the intronic CYP3A4*22 variant, which was &amp;gt;30x. Results Somatic and germline Aldy calls were compared for a total of 512 genotypes and 56 (11%) calls were discordant. Discordant calls were most common for CYP2B6 (23.4%), followed by CYP2D6 (14.1%), CYP2C19 (10.9%), CYP2C8 (6.3%), and DPYD (6.3%). In contrast, all Aldy calls were concordant for CYP3A5 and TPMT. 38 out of 64 subjects (59%) had discordant calls for at least one gene. The most common first cancer diagnoses in our cohort were colorectal (9.3%), breast (7.8%), and pancreatic (7.8%), and the rates of discordant Aldy calls did not differ by cancer type (p&amp;gt;0.05 for all cancer types). Based on our analyses of discordant calls, we anticipate that adjusting Aldy’s thresholds for variant calling may allow Aldy to determine genotypes from somatic WES data. Conclusion In most cases, genotype calls of drug metabolism genes from tumor DNA reflected the germline genotypes; however, additional work needs to be done to determine if the remaining discordant calls can be corrected by modifying the informatics tools or if they are due to somatic mutations. Citation Format: Wilberforce A. Osei, Tyler Shugg, Reynold C. Ly, Steven M. Bray, Benjamin A. Salisbury, Ryan R. Ratcliff, Victoria M. Pratt, Ibrahim Numanagić, Todd Skaar. Pharmacogenomics genotyping from clinical somatic whole exome sequencing: Aldy, a computational tool [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1151.
Abstract 968: Loss of glutathione peroxidase 2 promotes epithelial to mesenchymal transition and breast cancer metastasis
Authors: Zuen Ren, Huizhi Liang, Malindrie Dharmaratne, Miriam Morales-Gallego, Atefeh Taherian Fard, Jessica Mar, Kimita Suyama, Outhiriaradjou Benard, Michael B. Prystowsky, Larry Norton, Rachel B. Hazan
Journal: Cancer Research (2022)

Abstract The processes regulating tumor metastasis are multivariate and complex. Redox regulation of the tumor phenotype by GPx2 knockdown (KD) in breast cancer led us to uncover dramatic effects on spontaneous metastasis. Analysis of single cell RNA sequencing (scRNAseq) data from GPx2 KD tumor and control tumor, revealed that both tumors were comprised of several luminal-like tumor cell clusters and one mesenchymal-like cell cluster (cluster 3). Notably, GPx2 KD promoted a significant increase in the size of mesenchymal cells (cluster 3) relative to control, which might be due to the stimulation of epithelial-to-mesenchymal transition (EMT) in response to GPx2 loss. In support of this view, GPx2 KD stimulated an increase in mRNA expression of basal/mesenchymal (KRT5, KRT14, KRT17, Vimentin, Twist1, Twist2, CDH2) genes and a decrease in mRNA expression of epithelial/luminal (Cldn7 and Epcam) genes, especially in cluster 3. Moreover, GPx2 KD upregulated mRNA expression of basal/mesenchymal (Twist2, CDH2, and KRT14) genes in most luminal-like clusters expressing epithelial/luminal (Epcam, Cldn3/7, CDH1, KRT8/18) genes, implying these clusters may be undergoing EMT transition in a hybrid epithelial/mesenchymal state in response to GPx2 loss. Validation of these data in cell lines and tumors showed that GPx2 KD dramatically enhanced EMT via activation of ROS/HIF1α-mediated signaling. Importantly, these effects were reversed by GPx2 re-expression or HIF1α inhibition, which was capable of suppressing EMT and metastasis. Collectively, these results indicate that GPx2 loss promotes breast cancer metastasis by stimulating EMT due to HIF1α signaling, highlighting the impact of GPx2 and HIF1 on therapeutic intervention in metastasis. Citation Format: Zuen Ren, Huizhi Liang, Malindrie Dharmaratne, Miriam Morales-Gallego, Atefeh Taherian Fard, Jessica Mar, Kimita Suyama, Outhiriaradjou Benard, Michael B. Prystowsky, Larry Norton, Rachel B. Hazan. Loss of glutathione peroxidase 2 promotes epithelial to mesenchymal transition and breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 968.
Clinical Characteristics and Prognostic Importance of Left Ventricular Apical Aneurysms in Hypertrophic Cardiomyopathy
Authors: Deacon Z.J. Lee, Mahdi Montazeri, Roxana Bataiosu, Sara Hoss, Arnon Adler, Elsie T. Nguyen, Harry Rakowski, Raymond H. Chan
Journal: JACC. Cardiovascular imaging (2022)
Prognostic Value of Microvascular Resistance at Rest in Patients With Takotsubo Syndrome
Authors: Jordi Sans-Roselló, Estefanía Fernández-Peregrina, Albert Duran-Cambra, Jose Carreras-Mora, Alessandro Sionis, Jesús Álvarez-García, Hector M. García-García
Journal: JACC. Cardiovascular imaging (2022)
Abstract LB045: β-catenin antagonist peptide, ST316, attenuates Wnt-dependent oncogenic activity
Authors: Lila Ghamsari, Erin Gallagher, Emad Darvishi, Siok Leong, Mark Koester, Rick Ramirez, Jerel Gonzales, Gene Merutka, Barry Kappel, Jim A. Rotolo
Journal: Cancer Research (2022)

Abstract Constitutive activation of the Wnt/β-catenin signaling pathway underlines many breast and colorectal cancers, promoting cancer cell survival, proliferation and migration. B-cell CLL/lymphoma 9 protein (BCL9), a co-activator of β-catenin transcriptional activity, is overexpressed in many tumors and facilitates β-catenin nuclear localization. Disruption of the β-catenin and BCL9 interaction has been shown genetically to suppress oncogenic Wnt/β-catenin transcription, without impacting β-catenin homeostatic functions, and represents a powerful approach to inhibit this previously ‘undruggable’ target. Here, we investigate the impact of ST316, a peptide antagonist of β-catenin that inhibits its interaction with BCL9, on cells displaying hyperactivation of the Wnt/β-catenin pathway. Administration of ST316 to HCT116 human colorectal carcinoma cells, which carry a degradation-escape, gain-of-function mutation in β-catenin, dramatically reduced nuclear β-catenin localization. Furthermore, ST316-mediated loss of nuclear β-catenin was associated with a significant decrease in the expression of Wnt/β-catenin target genes in HCT116 cells stimulated with Wnt3a, including Axin2, hTCF7, Fox01 and CDK4. ST316 reduced β-catenin target gene expression by up to ∼70%, whereas no impact was observed following administration of a negative control peptide. A significant anti-proliferative and dose-dependent cytotoxic effect was observed on HCT116 cells 48 hours post ST316 exposure, with an EC50 of 4.4 µM, and on patient-derived, APC-mutant colorectal adenocarcinoma and breast carcinoma cells 72 hours post ST316 exposure, with EC50 values ranging from 1.5 to 2.6 µM. To extend these findings, we investigated the impact of ST316 on HCT116 tumors in vivo. ST316 (5 mg/kg) administered three times weekly by subcutaneous injection resulted in 99.6% tumor growth inhibition vs. vehicle controls (p&amp;lt;0.05), while a negative control peptide had no significant impact on tumor growth. These data demonstrate the potential of ST316 as a potent therapeutic candidate for Wnt/β-catenin-dependent cancers. Citation Format: Lila Ghamsari, Erin Gallagher, Emad Darvishi, Siok Leong, Mark Koester, Rick Ramirez, Jerel Gonzales, Gene Merutka, Barry Kappel, Jim A. Rotolo. β-catenin antagonist peptide, ST316, attenuates Wnt-dependent oncogenic activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB045.
Integrated use of PD-1 inhibition and transarterial chemoembolization for hepatocellular carcinoma: evaluation of safety and efficacy in a retrospective, propensity score-matched study
Authors: Brett Marinelli, Edward Kim, Antonio D'Alessio, Mario Cedillo, Ishan Sinha, Neha Debnath, Masatoshi Kudo, Naoshi Nishida, Anwaar Saeed, Hannah Hildebrand, Ahmed O Kaseb, Yehia I Abugabal, Anjana Pillai, Yi-Hsiang Huang, Uqba Khan, Mahvish Muzaffar, Abdul Rafeh Naqash, Rahul Patel, Aaron Fischman, Vivian Bishay, Dominik Bettinger, Max Sung, Celina Ang, Myron Schwartz, David J Pinato, Thomas Marron
Journal: Journal for ImmunoTherapy of Cancer (2022)

Immune checkpoint inhibitors (ICIs) have revolutionized treatment of advanced hepatocellular carcinoma. Integrated use of transarterial chemoembolization (TACE), a locoregional inducer of immunogenic cell death, with ICI has not been formally assessed for safety and efficacy outcomes.From a retrospective multicenter dataset of 323 patients treated with ICI, we identified 31 patients who underwent >1 TACE 60 days before or concurrently, with nivolumab at a single center. We derived a propensity score-matched cohort of 104 patients based on Child-Pugh Score, portal vein thrombosis, extrahepatic metastasis and alpha fetoprotein (AFP) who received nivolumab monotherapy. We described overall survival (OS), progression-free survival (PFS), objective responses according to modified RECIST criteria and safety in the multimodal arm in comparison to monotherapy.Over a median follow-up of 9.3 (IQR 4.0-16.4) months, patients undergoing multimodal immunotherapy with TACE achieved a significantly longer median (95% CI) PFS of 8.8 (6.2-23.2) vs 3.7 (2.7-5.4) months (log-rank 0.15, p<0.01) in the monotherapy group. Multimodal immunotherapy with TACE demonstrated a numerically longer OS compared with ICI monotherapy with a median 35.1 (16.1-Not Evaluable) vs 16.6 (15.7-32.6) months (log-rank 0.41, p=0.12). In the multimodal treatment group, there were three (10%) grade 3 or higher adverse events (AEs) attributed to immunotherapy compared with seven (6.7%) in the matched ICI monotherapy arm. There were no AEs grade 3 or higher attributed to TACE in the multimodal treatment arm. At 3 months following each TACE in the multimodal arm, there was an overall objective response rate of 84%. There were no significant changes in liver functional reserve 1 month following each TACE. Four patients undergoing multimodal treatment were successfully bridged to transplant.TACE can be safely integrated with programmed cell death 1 blockade and may lead to a significant delay in tumor progression and disease downstaging in selected patients.
Abstract 2401: Investigating the role of type II IL4 receptor in breast cancer brain metastasis
Authors: Wendy Bindeman, Demond Williams, Ebony Hargrove-Wiley, Barbara Fingleton
Journal: Cancer Research (2022)

Abstract Breast-to-brain metastasis is a devastating disease complication for which there are currently few treatment options. Among breast cancer subtypes, patients with triple-negative breast cancer (TNBC) and HER2+ breast cancer experience elevated rates of brain metastasis. The cytokines IL4 and IL13 are overexpressed by many human solid tumors. Both are associated with invasive and metastatic phenotypes; IL13 is additionally consequential in primary brain tumors. These cytokines signal through type I (IL4 only) and type II (IL4/IL13) IL4 receptors (IL4R). Importantly, expression of type II IL4R correlates with poor patient prognosis in basal-like (i.e., triple-negative) breast cancer, and HER2+ tumors display elevated type II IL4R expression. Our laboratory has shown that genetic loss of IL4R signaling in tumor cells attenuates lung and liver metastasis in mice. Additionally, we recently identified a role for IL4R signaling in modulating glycosylation in tumor cells. We hypothesize that IL4R signaling influences TNBC brain metastasis at least in part via modulating glycosylation. In a pilot mouse study, pharmacological blockade of IL4R after intracardiac injection of syngeneic TNBC cells resulted in attenuation of brain metastatic growth and circulating tumor cell burden. We have also observed significant changes in the expression of a sialyltransferase (ST8SIA1) that has been implicated in primary brain tumors, as well as in the abundance of several sialic acid-containing protein species in breast cancer cells following treatment with IL4 or IL13. Further, IL4 stimulation increases the overall glycosylation of several proteins of interest, including a glucose transporter and a glutamine transporter, without altering gene expression. Overall, our data suggest that type II IL4R signaling promotes metastasis, potentially through a mechanism involving protein glycosylation. Blockade of this receptor may be a useful therapeutic approach for patients with breast cancer brain metastases. Citation Format: Wendy Bindeman, Demond Williams, Ebony Hargrove-Wiley, Barbara Fingleton. Investigating the role of type II IL4 receptor in breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2401.
Abstract 4056: ONC201 in combination with carboplatin and etoposide as a novel triple drug treatment for small cell lung cancer (SCLC)
Authors: Young S. Lee, Lanlan Zhou, Christopher Azzoli, Wafik S. El-Deiry
Journal: Cancer Research (2022)

Abstract Lung cancer is the leading cause of cancer death in both men and women according to the American Cancer Society, with more deaths than colon, breast, and prostate cancer combined. Small cell lung cancer (SCLC) comprises about 10 to 15 percent of all lung cancer diagnoses. Frequent loss of RB1 and mutations in p53 in SCLC make it rather difficult to develop targeted therapies. Many current therapies rely on toxic chemotherapy or immunotherapy to combat the aggressive nature of SCLC; however, even with the advent of new therapies, the median survival rate has remained relatively low at 12 to 16 months. SCLC is also characterized by a high mutation rate, resulting in patients becoming increasingly resistant to treatments. This calls for a novel combination to extend patient life expectancy. ONC201 is an imipridone that is currently in clinical trials for its proapoptotic effects in several cancer types. We propose that combining ONC201 with standard first-line chemotherapeutic agents etoposide and carboplatin will result in a synergistic effect and serve as a novel treatment plan for SCLC patients. SCLC cell lines H1048 and H1105 were treated with the novel triple drug combination ONC201, etoposide, and carboplatin. Cell-Titer Glo cell viability assays were conducted for 72 hours to see the additive and/or synergistic effect of novel triple drug treatment. Western blots were also run to evaluate the expression of proapoptotic protein cleaved PARP or expression of cellular metabolic stress protein ATF4 to explore the synergistic effect of triple drug treatments in SCLC cell lines. Cell viability after the triple drug treatment in both cell lines H1048 and H1105 may indicate a potential synergistic effect. Preliminary western results indicate that the triple drug treatment results in an increase in cPARP or ATF4 expression relative to the vehicle, suggesting a synergistic effect of the triple drug treatment. We are currently exploring the novel combination and potential underlying mechanisms behind the synergistic effects of the triple drug treatment. Future studies will evaluate this triple drug combination treatment in mouse models of SCLC. Citation Format: Young S. Lee, Lanlan Zhou, Christopher Azzoli, Wafik S. El-Deiry. ONC201 in combination with carboplatin and etoposide as a novel triple drug treatment for small cell lung cancer (SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4056.